Enhancement of drug susceptibility of Mycobacterium avium by inhibitors of cell envelope synthesis

Abstract

Treatment of infections caused by Mycobacterium avium complex bacteria still remains a challenge since these organisms are resistant to a majority of antituberculous drugs. M. avium is very often linked with acquired immune deficiency syndrome-associated opportunistic infections. We earlier suggested that one of the strategies for circumventing multiple-drug resistance might be the enhancement of M. avium drug susceptibility by inhibiting the synthesis of the outermost layer of its envelope, which appears to act as an exclusionary barrier for drugs. In this investigation, we have examined this strategy by simultaneously using drugs and the following inhibitors of the M. avium cell envelope: m-fluoro-phenylalanine (an inhibitor of mycoside-C biosynthesis), DL-norleucine (an inhibitor of transmethylation reactions), ethambutol (an inhibitor of arabinogalactan synthesis), EDTA (a divalent-ion chelator), and colistin (an inducer of membrane flux of divalent cations). All the drugs were used in concentrations which were low enough for a possible medical application to be foreseen. This approach, tested on seven strains of the M. avium complex, showed that both m-fluoro-phenylalanine and ethambutol were interesting candidates because they caused significant enhancement of M. avium drug susceptibility.